This is a single-arm, single institution, phase II study of fludarabine monophosphate followed by Iodine I 131 Tositumomab for patients with previously untreated, advanced-stage (stage III or IV) low-grade, transformed low-grade and follicular non-Hodgkin's lymphoma. The primary objective of the study will be to evaluate the safety of this treatment combination and the secondary endpoint will be to evaluate efficacy.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
38
Tositumomab and Iodine I 131 Tositumomab
Number of Participants With Any Adverse Event (AE)
An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and does not necessarily have to have a causal relationship (association) with this treatment. Therefore, an AE was any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not it was considered to be related to the medicinal product. Laboratory abnormalities were recorded as AEs only if they were associated with clinical sequelae and/or required an intervention.
Time frame: First day of fludarabine cycle 1 to day prior to TST and iodine I 131 TST dosimetric dose (DD) (Week -16 to Week 1); Day of TST and iodine I 131 TST DD to database release (Week 1 to Week 520)
Number of Participants With Any Treatment-related Adverse Event (TRAE)
All noxious and unintended responses to a study treatment related to any dose were considered as TRAEs. A response to a study treatment indicates that a causal relationship between a study drug and an adverse event was at least a reasonable possibility, i.e., the relationship cannot be ruled out.
Time frame: First day of fludarabine cycle 1 to day prior to TST and iodine I 131 TST DD (Week -16 to Week 1); Day of TST and iodine I 131 TST DD to database release (Week 1 to Week 520)
Number of Participants With Any Grade 3 or Grade 4 Adverse Event
Adverse events were graded using the Common Toxicity Criteria from the Cancer Therapy Evaluation Program, Division of Cancer Therapy, National Cancer Institute. Grades: 0 = No adverse event or within normal limits; 1 = Mild adverse event; 2 = Moderate adverse event; 3 = Severe and undesirable adverse event; 4 = Life-threatening or disabling adverse event; 5 = Death related to adverse event.
Time frame: First day of fludarabine cycle 1 to day prior to TST and iodine I 131 TST DD (Week -16 to Week 1); Day of TST and iodine I 131 TST DD to database release (Week 1 to Week 520)
Number of Participants With Any Treatment-related Grade 3 or Grade 4 Adverse Event
All of the treatment-related grade 3 (severe and undesirable) and grade 4 (life-threatening or disabling) adverse events experienced by the participants were recorded.
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Time frame: First day of fludarabine cycle 1 to day prior to TST and iodine I 131 TST DD (Week -16 to Week 1); Day of TST and iodine I 131 TST DD to database release (Week 1 to Week 520)
Number of Participants With Any Serious Adverse Event (SAE)
An SAE was defined as any event occurring at any dose that results in any of the following outcomes: death, a life threatening adverse drug experience (at immediate risk of death from the experience as it occurred), inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity, or a congenital anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered to be a serious adverse drug experience when based upon appropriate medical judgment.
Time frame: First day of fludarabine cycle 1 to day prior to TST and iodine I 131 TST DD (Week -16 to Week 1); Day of TST and iodine I 131 TST DD to database release (Week 1 to Week 520)
Number of Participants With Any Treatment-related SAE
All of the treatment-related SAEs experienced by the participants were recorded.
Time frame: First day of fludarabine cycle 1 to day prior to TST and iodine I 131 TST DD (Week -16 to Week 1); Day of TST and iodine I 131 TST DD to database release (Week 1 to Week 520)
Number of Participants With the Indicated Grade 3 and Grade 4 AEs
AEs were graded using the Common Toxicity Criteria from the Cancer Therapy Evaluation Program, Division of Cancer Therapy, National Cancer Institute. Grades: 0 = No AE or within normal limits; 1 = Mild AE; 2 = Moderate AE; 3 = Severe and undesirable AE; 4 = Life-threatening or disabling AE; 5 = Death related to AE. mm, millimeters; mm\^3, millimeters cubed. Grade 3 and Grade 4 AEs are reported to focus on the most severe AEs.
Time frame: First day of fludarabine cycle 1 to day prior to TST and iodine I 131 TST DD (Week -16 to Week 1); Day of TST and iodine I 131 TST DD to database release (Week 1 to Week 520)
Number of Participants With the Indicated Treatment-related AEs Experienced by at Least 10% of Participants in the Combined Regimen
All noxious and unintended responses to a study treatment related to any dose were considered as TRAEs. A response to a study treatment indicates that a causal relationship between a study drug and an adverse event was at least a reasonable possibility, i.e., the relationship cannot be ruled out.
Time frame: First day of fludarabine cycle 1 to day prior to TST and iodine I 131 TST DD (Week -16 to Week 1); Day of TST and iodine I 131 TST DD to database release (Week 1 to Week 520)
Number of Participants Who Were Negative for Human Anti-murine Antibodies (HAMA) at Baseline (Study Entry) But Positive or Negative at Weeks 12 and 25 and at Months 12, 18, and 24
The administration of murine antibodies may form HAMA. A HAMA assay was performed using the ImmunoSTRIP HAMA IgG enzyme-linked immune absorbent assay by a central laboratory (Covance Classic Laboratory Services, Indianapolis, IN). Fludarabine, a known immunosuppressant, might decrease HAMA production in addition to reducing bone marrow involvement. To be "positive," a participant had to have a positive HAMA assessment at any follow-up visit (Weeks 12 and 25; Months 12, 18, and 24).
Time frame: Day 1 to Day 730 (24 Months) after receiving the dosimetric dose
Time to HAMA Positivity From the First TST/I 131 TST Dosimetric Dose for the Participants Achieving HAMA Positivity
Kaplan-Meier estimates of the time to HAMA positivity (days from the first fludarabine dose) was determined for participants who converted to HAMA positivity.
Time frame: Day 1 to Day 730 (24 Months) after receiving the dosimetric dose
Number of Participants With Elevated Thyroid-Stimulating Hormone (TSH) Levels at Baseline (Study Entry) and Weeks 25, 52, 78, 104, 130, 156, 182, 208, 234, 260, 286, 312, 364, 416, 468, and 512
The number of participants with elevated TSH levels is reported. An elevated TSH level indicates that an insufficient amount of the thyroid hormone is being produced. Insufficient thyroid hormone production is known as hypothyroidism. The normal range of TSH is between 0.2 and 6.1 milliunits per liter (mU/L).
Time frame: Baseline (Week -16) and Weeks 25, 52, 78, 104, 130, 156, 182, 208, 234, 260, 286, 312, 364, 416, 468, and 512
Number of Participants With Thyroid Medication Use Prior to the Therapeutic Dose
Thyroid medication included any prescribed medication for the treatment of thyroid dysfunction.
Time frame: Baseline (study entry; Week -16) and Week 2 to Week 3 (prior to the therapeutic dose)
Time to Nadir for Hematological Parameters: Absolute Neutrophil Count (ANC), Hemoglobin, and Platelets
Nadir was defined as the lowest laboratory value recorded up to 120 days following the therapeutic dose (or dosimetric dose for participants who did not receive the therapeutic dose).
Time frame: up to 120 days following the therapeutic dose (or dosimetric dose for participants who did not receive the therapeutic dose)
Nadir Values for Absolute Neutrophil Count (ANC)
Nadir was defined as the lowest laboratory value recorded up to 120 days following the therapeutic dose (or dosimetric dose for participants who did not receive the therapeutic dose).
Time frame: up to 120 days following the therapeutic dose (or dosimetric dose for participants who did not receive the therapeutic dose)
Nadir Values for Hemoglobin
Nadir was defined as the lowest laboratory value recorded up to 120 days following the therapeutic dose (or dosimetric dose for participants who did not receive the therapeutic dose).
Time frame: up to 120 days following the therapeutic dose (or dosimetric dose for participants who did not receive the therapeutic dose)
Nadir Values for Platelet Count
Nadir was defined as the lowest laboratory value recorded up to 120 days following the therapeutic dose (or dosimetric dose for participants who did not receive the therapeutic dose).
Time frame: up to 120 days following the therapeutic dose (or dosimetric dose for participants who did not receive the therapeutic dose)
Number of Participants With Any Grade 3 or Grade 4 Toxicity (AE) for Hematological Parameters (Absolute Neutrophil Count [ANC], Hemoglobin, and Platelets)
Adverse events were graded using the Common Toxicity Criteria from the Cancer Therapy Evaluation Program, Division of Cancer Therapy, National Cancer Institute. Grades (G): 0=No AE or within normal limits; 1=Mild AE; 2=Moderate AE; 3=Severe and undesirable AE; 4=Life-threatening or disabling AE; 5=Death related to AE. ANC (10\^3/mm\^3): G1=1.5 to \<2.0, G2=1.0 to \<1.5, G3=0.5 to \< 1.0, G4=\<0.5. Hemoglobin (g/dL): G1=10.0 to \<12.0, G2=8.0 to \<10.0, G3=6.5 to \<8.0, G4=\< 6.5. Platelets (10\^3/microliter): G1=75 to \<150, G2=50 to \<75, G3=25 to \<50, G4=\<25.
Time frame: First day of fludarabine cycle 1 to day prior to TST and iodine I 131 TST dosimetric dose (DD) (Week -16 to Week 1); Day of TST and iodine I 131 TST DD to database release (Week 1 to Week 520)
Duration of Any Grade 3 or Grade 4 Toxicity for Hematological Parameters: Absolute Neutrophil Count (ANC), Hemoglobin, and Platelets
Adverse events were graded using the Common Toxicity Criteria from the Cancer Therapy Evaluation Program, Division of Cancer Therapy, National Cancer Institute. Grades (G): 0=No AE or within normal limits; 1=Mild AE; 2=Moderate AE; 3=Severe and undesirable AE; 4=Life-threatening or disabling AE; 5=Death related to AE. ANC (10\^3/mm\^3): G1=1.5 to \<2.0, G2=1.0 to \<1.5, G3=0.5 to \< 1.0, G4=\<0.5. Hemoglobin (g/dL): G1=10.0 to \<12.0, G2=8.0 to \<10.0, G3=6.5 to \<8.0, G4=\< 6.5. Platelets (10\^3/microliter): G1=75 to \<150, G2=50 to \<75, G3=25 to \<50, G4=\<25.
Time frame: First day of fludarabine cycle 1 to day prior to TST and iodine I 131 TST dosimetric dose (DD) (Week -16 to Week 1); Day of TST and iodine I 131 TST DD to database release (Week 1 to Week 520)
Number of Participants With Any Infection at Week 16 Post-Fludarabine Treatment and Week 13 Post-TST Treatment Detected by Laboratory Culture of Participant Sample or Investigator Report
An infection is the colonization of a host organism by a parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease. Colloquially, infections are usually considered to be caused by microscopic organisms or microparasites like viruses, bacteria, and viroids, although larger organisms such as macroparasites and fungi can also infect.
Time frame: Week 16 Post-Fludarabine Treatment (Week -16 to Week 0); Week 13 Post-TST Treatment (Week 1 to Week 13)
Number of the Indicated Type of Infection Reported by Investigator Based on Laboratory Testing at Week 16 Post-Fludarabine (Fl) Treatment and Week 13 Post-TST Treatment
An infection is the colonization of a host organism by a parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease. Colloquially, infections are usually considered to be caused by microscopic organisms or microparasites like viruses, bacteria, and viroids, although larger organisms such as macroparasites and fungi can also infect.
Time frame: Week 16 Post-Fludarabine Treatment (Week -16 to Week 0); Week 13 Post-TST Treatment (Week 1 to Week 13)
Number of Participants With a Culture Obtained for Infection at Week 16 Post-Fludarabine (Fl) Treatment and Week 13 Post-TST Treatment
Specimen samples of the body fluid are cultured for testing whether the infectious organism is present and grown in the culture media to assess the growth pattern of the organisms present in the specimen.
Time frame: Week 16 Post-Fludarabine Treatment (Week -16 to Week 0); Week 13 Post-TST Treatment (Week 1 to Week 13)
Number of Participants With Positive Culture Results for Infections at Week 16 Post-Fludarabine (Fl) Treatment and Week 13 Post-TST Treatment
The culture results could be positive or negative. The positive culture results indicates that the tested participant have the infection under investigation so therapeutic treatment with anti-infective is required.
Time frame: Week 16 Post-Fludarabine Treatment (Week -16 to Week 0); Week 13 Post-TST Treatment (Week 1 to Week 13)
Number of Participants With an Anti-infective Administered at Week 16 Post-Fludarabine (Fl) Treatment and Week 13 Post-TST Treatment
Anti-infectives are capable of acting against infection, by inhibiting the spread of an infectious agent or by killing the infectious agent outright. Anti-infective is a general term that encompasses antibacterials, antibiotics, antifungals, antiprotozoans, and antivirals.
Time frame: Week 16 Post-Fludarabine Treatment (Week -16 to Week 0); Week 13 Post-TST Treatment (Week 1 to Week 13)
Number of Participants Who Received Any Supportive Care After Fludarabine Treatment and After TST Treatment
Supportive care involves interventions that help the participants to achieve comfort but do not affect the course of a disease.
Time frame: First day of fludarabine cycle 1 to day prior to TST and iodine I 131 TST DD (Week -16 to Week 1); Day of TST and iodine I 131 TST DD to database release (Week 1 to Week 520)
Number of Participants Receiving the Indicated Type of Supportive Care After Fludarabine Treatment and After TST Treatment
Supportive care involves interventions that help the participants to achieve comfort but do not affect the course of a disease. Supportive care involved administration of granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF), red blood cell (RBC) transfusions, erythropoietin, and platelet transfusions.
Time frame: First day of fludarabine cycle 1 to day prior to TST/I 131 TST dosimetric dose (Week -16 to Week 1); Day of TST/I 131 TST dosimetric dose to database release (Week 1 to Week 520)
Number of Participants With the Investigator-assessed Confirmed Responses of Complete Response (CR), Clinical Complete Response (CCR), and Partial Response (PR)
CR: Complete resolution of disease-related (DR) radiological abnormalities; disappearance of non-Hodgkin's lymphoma-related signs/symptoms. CCR: Complete resolution of DR symptoms except for residual scar tissue. PR: 50% reduction in the sum of the products of the longest perpendicular diameters of measurable lesions with no new lesions. A confirmed response (resp.) (CR/CCR/PR) had to be confirmed by a consecutive resp. (\>=28 days later) that was the same/better. Individual confirmed resp. data only counts that resp. confirmed by the same resp.; not all possible combinations are represented.
Time frame: First day of fludarabine cycle 1 to day prior to TST/I 131 TST dosimetric dose (Week -16 to Week 1); Day of TST/I 131 TST dosimetric dose to database release (Week 1 to Week 520)
Number of Participants With the Investigator-assessed Unconfirmed Responses of Complete Response (CR), Clinical Complete Response (CCR), and Partial Response (PR)
CR: Complete resolution of disease-related (DR) radiological abnormalities; disappearance of non-Hodgkin's lymphoma-related signs/symptoms. CCR: Complete resolution of DR symptoms except for residual scar tissue. PR: 50% reduction in the sum of the products of the longest perpendicular diameters of measurable lesions with no new lesions.
Time frame: First day of fludarabine cycle 1 to day prior to TST/I 131 TST dosimetric dose (Week -16 to Week 1); Day of TST/I 131 TST dosimetric dose to database release (Week 1 to Week 520)
Number of Participants With Progression of Disease
Progression of disease is defined as a 50% increase from nadir of the sum of the longest perpendicular diameters of all measurable lesions or the appearance of any new lesion. Individual lesions must be \>2 cm in diameter per radiographic evaluation or \>1 cm in diameter by physical examination. All participants without progression of disease were censored.
Time frame: First day of fludarabine cycle 1 to day prior to TST/I 131 TST dosimetric dose (Week -16 to Week 1); Day of TST/I 131 TST dosimetric dose to database release (Week 1 to Week 520)
Duration of Response for All Confirmed Responders
Duration of response was defined as the time from the first documented response to the first documented disease progression. Partial Response (PR): 50% reduction in the sum of the products of the longest perpendicular diameters of all measurable lesions with no new lesions. Responders are the participants with CR, or CCR, or PR.
Time frame: First day of fludarabine cycle 1 to day prior to TST/I 131 TST dosimetric dose (Week -16 to Week 1); Day of TST/I 131 TST dosimetric dose to database release (Week 1 to Week 520)
Number of Participants With Progressive Disease (PD)
PD is defined as a 50% increase from nadir of the sum of the longest perpendicular diameters of all measurable lesions or the appearance of any new lesion. Individual lesions must be \>2 cm in diameter per radiographic evaluation or \>1 cm in diameter by physical examination.
Time frame: First day of fludarabine cycle 1 to day prior to TST/I 131 TST dosimetric dose (Week -16 to Week 1); Day of TST/I 131 TST dosimetric dose to database release (Week 1 to Week 520)
Time to Disease Progression or Death
Time to progression is the time from the treatment start date to the first documented disease progression or death. Disease progression: 50% increase from nadir of the sum of the longest perpendicular diameters of all measurable lesions or the appearance of any new lesion. Individual lesions must be \>2 cm in diameter per radiographic evaluation or \>1 cm in diameter by physical examination.
Time frame: First day of fludarabine cycle 1 to day prior to TST/I 131 TST dosimetric dose (Week -16 to Week 1); Day of TST/I 131 TST dosimetric dose to database release (Week 1 to Week 520)
Number of Participants With a Treatment Failure
Treatment failure is defined as the occurrence of treatment withdrawal, a decision to seek additional therapy, study removal, progression, alternative therapy for lymphoma, or death.
Time frame: First day of fludarabine cycle 1 to day prior to TST/I 131 TST dosimetric dose (Week -16 to Week 1); Day of TST/I 131 TST dosimetric dose to database release (Week 1 to Week 520)
Time to Treatment Failure
Time to treatment failure is defined as the time from the treatment start date to the first occurrence of treatment withdrawal, a decision to seek additional therapy, study removal, progression, alternative therapy for lymphoma, or death.
Time frame: First day of fludarabine cycle 1 to day prior to TST/I 131 TST dosimetric dose (Week -16 to Week 1); Day of TST/I 131 TST dosimetric dose to database release (Week 1 to Week 520)
Number of Participants Who Died During Their Participation in the Study
Participants who died during the study period were evaluated for the overall survival endpoint.
Time frame: Day of TST/I 131 TST dosimetric dose to date of database release (Week 1 to Week 520); First day of fludarabine cycle 1 to date of database release (Week -16 to Week 520)
Time to Death of Participants During Their Participation in the Study
Time to death is defined as the time from the treatment start date to the date of death.
Time frame: Day of TST/I 131 TST dosimetric dose to date of database release (Week 1 to Week 520); First day of fludarabine cycle 1 to date of database release (Week -16 to Week 520)